http://www.sciam.com/article.cfm?id=microbicides-docs-still-hopeful&print=true

Antiretroviral (ARV) drugs have transformed HIV infection from a death sentence to a manageable chronic illness for millions worldwide. Now, scientists are testing whether ARVs can be used as microbicides, taken orally or applied vaginally as a gel or foam to prevent the transmission of the AIDS-causing human immunodeficiency virus.

If ARVs are proved as effective as microbicides, they have the potential to dramatically curb HIV infection rates. This is especially true in sub-Saharan Africa where women, who comprise nearly 61 percent of the adults living with HIV there, are eager for products besides condoms that they can use to protect themselves against the disease.

"I think it is very exciting to be integrating microbicides with drugs that have proven to work for treatment," says Roberta Black, chief of the Microbicide Research Branch at the National Institute for Allergy and Infectious Disease (NIAID) in Bethesda, Md. "This really jump-starts research efforts."

Microbicide research is at a crossroads as scientists begin testing the next generation of these drugs in the wake of a series of high-profile failures, including three late-stage clinical trials that were halted in the past year because the tested drug was found to be ineffective and, in one case, actually raised the risk of HIV transmission.

The latter trial, involving nearly 1,400 women in Durban, South Africa; Kampala, Uganda; Cotonou, Benin; Chennai, India; and Karnataka, India, was stopped last year when researchers realized the microbicide gel, made up of cellulose sulfate, not only failed to prevent HIV infection, but upped participants' risk of acquiring the virus. Forty-one women contracted HIV during the trial—25 in the cellulose sulfate gel group and 16 in the placebo gel group.

Carraguard, a seaweed-based microbicide tested by the Population Council, a nonprofit biomedical research group based in New York City, failed to show efficacy in a study carried out between 2004 and 2007 on 6,200 women. Carraguard is a polyanion, meaning that it carries a negative electrical charge that attracts HIV, whose surface is positively charged. The idea was that polyanions could prevent the virus from attaching to the host cell.

Almost simultaneously, last February in the U.K., the Microbicides Development Programme at Imperial College London announced that it was stopping one arm of a trial of another polyanion, PRO-2000, because the product was unlikely to show any benefit.

Two other compounds that showed early promise—nonoxynol-9 and Savvy—have also proved lackluster in recent years. Both are detergents, common agents used in spermicides, that disrupt HIV in test tubes, but in human microbicide trials they did not stop HIV transmission.

"It's very easy to get depressed," says Polly Harrison, founder and director of the Alliance for Microbicide Development, a Silver Spring, Md.–based nonprofit that advocates for the worldwide development of the products. "But the field has rallied and dusted itself off."

The reason for the rally isARVs. Two classes are in development as microbicides: entry inhibitors that prevent the virus from attaching to target cell surfaces or stop it from entering the cell after attachment, and reverse transcriptase inhibitors (RTIs) that block virus from replicating itself if it succeeds in entering a cell.

Some 40 microbicide products, including those whose active ingredient are ARVs, are currently in development around the world, according to the Alliance for Microbicide Development. Of these, 10 products have been shown to be safe and effective in animal trials and are being tested in humans in the U.S., Africa and India, according to the Center for AIDS Programme of Research (CAPRISA) in Congella, South Africa.

The ARV drug that holds the most promise is tenofovir, an RTI manufactured under the brand name Viread by Gilead Sciences. It is best known as the combination therapy pill, Truvada. The U.S. National Institutes of Health (NIH) and CAPRISA are set to conduct separate human trials of oral and topical tenofovir. NIH is currently recruiting up to 4,200 high-risk women (it hasn't yet said where) to test the gel and pill forms in a two-year trial set to begin in July. The CAPRISA trial of some 1,000 high-risk South African women began in May 2007 and is set to run through the end of next year.

There are about six ARV clinical trials underway in the United States, Africa and India. Among other drugs being tested: Dapivirine and Maraviroc, an RTI and an entry inhibitor, respectively. The International Partnership for Microbicides, a nonprofit drug development group in Silver Springs, Md., is conducting trials on Dapivirine gels and vaginal rings — thin, transparent rings inserted into the vagina that release medications over a month or more. (Vaginal rings are are already available as birth control, such as the product NuvaRing.)

The Partnership's CEO, microbiologist Zeda Rosenberg, says ARVs are promising because they last longer in the body than the compounds used in previous microbicides. The idea is that women could apply an ARV microbicide gel once a day or less and it would still be effective in preventing HIV transmission during a sexual encounter within 12 to 24 hours. To date, the gels tested had to be applied just before sex.

"Early-generation microbicides were coitally dependent, meaning they had to be used just prior to sex," Rosenberg says.

Divorcing microbicide use from sexual activity could help researchers sort out ineffective products from those that simply aren't being used properly by trial participants. "You cannot watch people apply vaginal microbicide right before they have sex," Harrison says.

They can, however, supervise application in the clinic on a daily basis if the product is longer lasting. A crucial recent development has been production of a gel out of ARVs that could be applied once a day and retains effectiveness regardless of climate. The gels also need to be safe. Some earlier microbicides caused vaginal inflammation. So far, two promising tenofovir gels have been produced, Rosenberg says.

In September, the Contraceptive Research and Development program (CONRAD) in Arlington, Va., a not-for-profit drug research organization affiliated with Eastern Virginia Medical School received a five-year, $100-million grant from the U.S. Agency for International Development (USAID) to test a tenofovir gel, develop new biomarkers (which tell researchers that disease is present so they know if a preventative measure worked to block transmission), and refine mouse modeling for microbicides, which, like most other drugs, are tested on mice and other animals before human trials. But many researchers say these need to be improved.

"Currently there are no markers or models that allow us to predict the safety and efficacy of a microbicide candidate with accuracy," says Henry Gabelnick, executive director of CONRAD. Some scientists are concerned that using ARVs for prevention could increase the spread of HIV resistance, because their use might boost transmission of naturally resistant variants of the disease. For instance, the use of the ARV drug nevirapine to prevent mother-to-child HIV transmission carries the risk of promoting drug-resistant virus.

It's unknown whether topically applied ARVs used in prevention would enter the human bloodstream at levels so that if a person does contract HIV, that same ARV would be useless in fighting the disease. There is concern that using ARVs for prevention could drive up human resistance to these medications, in a similar way that using antibiotics to fight common colds can lead to their ineffectiveness in fighting bacterial infections later. "This issue needs to be studied carefully in both nonhuman primates and humans before large-scale clinical trials are commenced," wrote 15 prominent U.S. and Canadian AIDS researchers in a paper published in the July 25 issue of Science.

In the harshly worded article, the researchers called for "some serious soul searching within the microbicide field," including better management and collaboration and more attention paid to underlying science, such as more rigorous testing on animals and trying out a variety of molecules that attack HIV at different points in the replication cycle of the virus in stead of focusing on just one strategy.

"We're still very hopeful that an effective microbicide will come out of this," says Robert Grant, lead author of the article and an immunologist at the Gladstone Institute of Virology and Immunology at the University of California, San Francisco. "At this stage, I think we should keep as many options open as possible. We do not have a proven concept."

He warns that it would be a mistake for researchers to invest all of their time and resources into ARVs, given that "It's not precisely known whether ARVs will work for prevention."

To date, no microbicide has worked successfully to prevent the spread of HIV. But, like efforts to develop an HIV vaccine, hope keeps researchers trying and donors giving, says Anna Forbes, deputy director of the Global Campaign for Microbicides, a Washington, D.C.–based coalition of 300 nongovernmental organizations working on the issue. "It would change the landscape considerably for women," Forbes says. "Think about the difference the Pill made in a decade. Microbicides have that same potential."